JP2003503405A - Benzamide derivatives - Google Patents

Abstract

(57) [Summary] The present invention relates to a compound represented by the general formula (I): Wherein R ¹ and R ² together form a benzene ring, R ³ is hydrogen, R ⁴ and R ⁵ are each hydrogen, R ⁶ and R ⁷ are each hydrogen, R ⁸ And R ⁹ together form a benzene ring or the like, and A represents a lower alkylene group. A novel benzamide derivative having vasopressin antagonistic activity and the like, a pharmaceutically acceptable salt thereof, a production method thereof, and a pharmaceutical composition containing the same.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to novel benzamide derivatives useful as pharmaceuticals and pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION Several benzamide derivatives are known, for example PCT International Publication WO 91/055.
49, WO95 / 29152 and WO96 / 41795, EP Application Publication 0620216 and Japanese Patent Application Publication H8-143565,
It is known as a vasopressin antagonist.

DISCLOSURE OF THE INVENTION The present invention relates to benzamide derivatives and pharmaceutically acceptable salts thereof.

More specifically, the present invention provides vasopressin antagonistic activity, vasodilatory activity, antihypertensive activity,
Novel benzamide derivatives having hepatic carbohydrate release inhibitory activity, glomerular stromal cell growth inhibitory activity, aquatic diuretic activity, platelet aggregation inhibitory activity, oxytocin antagonistic activity, and their pharmaceutically acceptable salts, containing them Pharmaceutical composition for human and animal, hypertension, heart failure, renal failure, edema, ascites, vasopressin secretion abnormality syndrome, cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory disorder, cerebrovascular disease (for example, brain edema). , Cerebral infarction, etc., Meniere's syndrome (eg, Meniere's disease, etc.), motion sickness and / or the like. Further, the target compound is a visual impairment caused by ocular circulation disorder (for example, intraocular hypertension, glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuritis, iridocyclitis, retinal artery occlusion, retinal vein thrombosis. , Diabetic retinitis and choroidal disease) and visual impairment associated with ciliary stretch (eg myopia) and / or treatment.

One object of the present invention is to provide new and useful benzamide derivatives having the above activity.

[0006] Another object of the present invention is to provide a method for producing the benzamide derivative and salts thereof.

Still another object of the present invention is to provide a pharmaceutical composition containing the benzamide derivative and pharmaceutically acceptable salts thereof as an active ingredient.

Another object of the present invention is to provide a method for treating and / or preventing the above-mentioned diseases in humans or animals using the benzamide derivatives and pharmaceutically acceptable salts thereof. .

[0009]   The object of the present invention is that the benzamide derivatives are novel and have the following general formula (I)

[0010]

[Chemical 8]

Wherein R ¹ and R ² together form a benzene, pyridine or thiophene ring, each of which may be substituted with one or more suitable substituents, R ³ Is hydrogen or a lower alkoxy group, R ⁴ and R ⁵ are each hydrogen or together form a bond, R ⁶ and R ⁷ are each hydrogen or together form oxo. , R ⁸ and R ⁹ together form a benzene ring, which benzene ring may be substituted with one or more suitable substituents, A represents a lower alkylene group, respectively. ] The compound and its pharmaceutically acceptable salt represented by these.

The target compound (I) or a salt thereof can be produced by the methods shown by the following reaction formulas.

[0013] Manufacturing method 1

[Chemical 9]

[0014]

[Chemical 10]

[0015] Manufacturing method 2

[Chemical 11]

(In the above formulas, R ¹ , R ² , R ³ , R ⁸ , R ⁹ and A are as defined above, and R ¹⁰ is a lower alkyl group.) In the above and following descriptions, preferred examples of various definitions within the scope of the present invention will be described in detail below.

“Lower” means a group having 1 to 6 carbon atoms unless otherwise specified.
Suitable "lower alkyl group" includes straight chain or branched C ₁ -C ₆ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, ethylpropyl, hexyl and the like. It is possible and preferable is ethyl.

Suitable “lower alkoxy group” includes methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tertiary butoxy,
Linear or branched C ₁ -C ₆ alkoxy such as pentyloxy and hexyloxy can be mentioned, and methoxy can be mentioned as a preferable example.

Suitable "lower alkylene group" may include straight chain or branched C ₁ -C ₆ alkylene such as methylene, ethylene, propylene, trimethylene, ethylethylene, tetramethylene, pentamethylene and hexamethylene. As a preferable example, tetramethylene can be mentioned.

Suitable “halogen” may include fluorine, chlorine, bromine and iodine.

“Benzene, pyridine or thiophene ring in R ¹ and R ² , each of which may be substituted with one or more suitable substituents” and “one or more in R ⁸ and R ⁹ Preferred examples of "suitable substituents" in the expression "benzene ring optionally substituted with further suitable substituents" include lower alkyl, lower alkoxy, halogen, hydroxy and the like. Can be lower alkyl.

Preferred compounds (I) include a benzene ring formed by R ¹ and R ² together, a lower alkoxy for R ³ , hydrogens for R ⁴ and R ⁵ ,
Each hydrogen in R ⁶ and R ^7, benzene ring formed by R ⁸ and R ⁹ together, and tetramethylene in A; or benzene formed by R ¹ and R ² together A ring, a lower alkoxy in R ³ , a bond formed by R ⁴ and R ^{5 taken} together, an oxo formed by R ⁶ and R ^{7 taken} together, a bond formed by R ⁸ and R ^{9 taken} together And a compound having tetramethylene in A.

More preferred compound (I) is a benzene ring formed by R ¹ and R ² together, a lower alkoxy in R ³ , a hydrogen atom in R ⁴ and R ^5, and a hydrogen atom in R ⁶ and R ⁷ . Mention may be made of the respective hydrogen, the benzene ring formed by R ⁸ and R ^{9 taken} together, and the tetramethylene in A.

Suitable pharmaceutically acceptable salts of the object compounds (I) are the customary non-toxic salts, which are acid addition salts, for example inorganic acid addition salts (for example hydrochlorides, hydrobromides, iodosalts). Hydrohydrates, sulfates, phosphates, etc., organic acid addition salts (eg formate, acetate,
Trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.) and the like. The production method of the target compound (I) is described in detail below.

Production Method 1 The object compound (Ia) or a salt thereof is a compound (II) or a salt thereof.
It can be produced by reacting with III) or a salt thereof. Suitable salts of the compounds (Ia), (II) and (III) include the compound (I
The same thing as illustrated by the above) can be mentioned. The reaction is usually performed in a conventional solvent such as dioxane, tetrahydrofuran, toluene, xylene or other organic solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under heating or heating.

Production Method 2 The object compound (Ib) or a salt thereof can be produced by reacting the compound (Ia) or a salt thereof with a reducing agent. Suitable salts of the compounds (Ia) and (Ib) may be the same as those exemplified for the compound (I). Suitable reducing agents include diborane, borane or a complex thereof (for example borane-
Tetrahydrofuran complex etc.) and the like. The reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran or other organic solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is carried out under cooling or heating.

The compound obtained according to the above production method can be separated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation and the like.

Compound (I) and other compounds may have one or more stereoisomers or geometric isomers based on asymmetric carbon atoms and double bonds, all of these isomers and Mixtures of are also within the scope of the invention.

Further, a solvate of compound (I) or a pharmaceutically acceptable salt thereof [eg, an inclusion compound (eg, hydrate)] is also included in the scope of the present invention.

The objective compound (I) and pharmaceutically acceptable salts thereof have vasopressin antagonistic activity, vasodilatory activity, antihypertensive activity, intrahepatic glucose release inhibitory activity, glomerular stromal cell growth inhibitory activity, aquaretic activity, It has activities such as platelet aggregation inhibitory activity and oxytocin antagonism, and it has high blood pressure in humans and animals, heart failure, renal failure, edema, ascites, vasopressin secretion abnormality syndrome, cirrhosis, hyponatremia, hypokalemia, diabetes, circulation. It is useful for treating and / or preventing a disorder, cerebrovascular disease (eg, cerebral edema, cerebral infarction, etc.), Meniere's syndrome (eg, Meniere's disease, etc.), motion sickness and the like. Further, the target compound is a visual impairment caused by ocular circulation disorder (for example, intraocular hypertension, glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuritis, iridocyclitis, retinal artery occlusion, retinal vein thrombosis. , Diabetic retinitis and choroidal disease) and visual impairment associated with ciliary stretch (eg myopia) and / or treatment.

In order to show the usefulness of the target compound (I), the pharmacological test data of the compound (I) are shown below.

Test 1 Vasopressin 1 (V1) Receptor Binding (i) Test Method Blood was collected from a healthy subject by venipuncture. Whole blood was centrifuged at 200 xg for 10 minutes to prepare Platelet Rich Plasma (PRP). PRP 3 at 45,000xg
Centrifuge for 0 minutes. The residual pellet was mixed with 10 volumes of ice-cold 100 mM Tris-HCl (p
H7.4) buffer (5 mM MgCl ₂ , 0.1% bovine serum albumin and 1 m
M EDTA) and centrifuged at 45,000 xg for 30 minutes.
The final pellet was resuspended in 100 mM Tris-HCl buffer. The resulting membrane product was immediately used for binding assay.

1.5 nM ³ H vasopressin (40-87 Ci / mmole, New England Nuclear (New E) in 100 mM Tris-HCl (pH 7.4) buffer.
competition assay was carried out at equilibrium (15 minutes at 30 ° C.). Nonspecific binding was determined using 1 μM vasopressin. After incubation, ice-cooled 100 mM Tris-HCl (pH 7.4) buffer 5 m
The reaction was stopped by the addition of 1 and then rapidly filtered through a Whatman glass filter (GF / C). The filter was washed twice with the same buffer. Glass filters were mixed with liquid scintillation cocktail and radioactivity was measured in a liquid scintillation counter. The competitive activity of the test compound was expressed as an IC ₅₀ value.

[0034] (Ii) Test result

[Table 1]

Test 2 Vasopressin 2 (V2) Receptor Binding (i) Test Method For binding assay, the receptor cDNA was used as a Chinese hamster ovary (CHO).
) It was continuously expressed in cells. Transfection of CHO cells with a vector inducing expression of the human V2 receptor cDNA and establishment of a clonal cell line expressing the human V2 receptor has been described essentially above (Nakajima).
Y et al., J. Biol. Chem. , 1992, 267, 2437),
I did.

Cells transfected with DNA were harvested and treated with 25 mM Tris-HCl (pH
7.4) Homogenized in ice-cold 250 mM sucrose buffer containing 10 mM MgCl ₂ , 1 mM EDTA and 5 μg / ml p-amidinophenylmethylsulfonylfluoride (A-PMSF). The homogenate was centrifuged at 500 xg for 10 minutes. The supernatant was centrifuged at 100,000 xg for 1 hour. The final pellet was mixed with 25 mM Tris-HCl (pH 7.4) buffer (10 mM MgCl ₂
1 mM EDTA and 5 μg / ml of A-PMSF) and suspended in small aliquots at −80 ° C.

100 mM Tris-HCl (pH 7.4) buffer (5 mM MgCl ₂ , 5 μg
/ Ml A-PMSF, 4 μg / ml leupeptin, 40 μg / ml bacitracin, 20 μg / ml chymostatin and 0.1% bovine serum albumin in 0.5 nM ³ H vasopressin (40-87 Ci / mmole, New England Nuclear,
Competitive assays were performed at equilibrium (22 ° C for 2 hours). Nonspecific binding was determined using 1 μM vasopressin. After incubation, the reaction mixture was rapidly filtered through a Whatman glass filter (GF / C). The filter was washed twice with the same buffer. Radioactivity was measured with a liquid scintillation counter. The competitive activity of the test compound was expressed as an IC ₅₀ value.

[0038] (Ii) Test result

[Table 2]

For the treatment, the compound (I) of the present invention is used as an active ingredient of one of the above compounds, an organic or inorganic solid suitable for oral, parenteral, external (topical) or intraocular administration, It can be used in the form of a pharmaceutical preparation containing a pharmaceutically acceptable carrier such as a semisolid or liquid excipient. This pharmaceutical preparation includes capsules, tablets, dragees,
It may be granules, suppositories, solutions, lotions, suspensions, emulsions, ointments, gels, eye drops and the like. If desired, the above-mentioned preparations may be mixed with auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other conventional additives.

The dose of compound (I) varies depending on the age and symptoms of the patient, but for the treatment of the above-mentioned diseases, an average single dose of compound (I), about 0.1 mg, 1 mg, 10 mg, 5
0 mg, 100 mg, 250 mg, 500 mg and 1000 mg are effective. Generally, an amount of 0.1 mg to about 1,000 mg per day may be administered per person.

[0041]   The following Production Examples and Examples are provided to illustrate the present invention.

Production Example 1 2-Methoxy-4- (2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonylbenzoic acid (1.50 g) in dichloromethane (18 m
To a cooled solution in l) thionyl chloride (0.584 ml), imidazole (803
mg) and triethylamine (2.12 ml) were added and the reaction mixture was stirred at room temperature for 1 hour. Then magnesium chloride (443 mg) and triethylamine (0.6
42 ml), potassium ethylmalonate (1.58 g) and N, N-dimethylformamide (1.8 ml) were added to the mixture. After 2 hours, 1N hydrochloric acid was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (chloroform to chloroform: methanol = 10: 1) to give 1- [3-methoxy-
4- (Ethoxycarbonylacetyl) benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepine (1.8 g) was obtained. NMR (CDCl ₃ , δ): 1.18 (3H, t, J = 7.5Hz), 1.54 (1H, m), 1.91-2.17 (3H, m),
2.74-3.11 (3H, m), 3.70 (3H, s), 3.88 (2H, s), 4.13 (2H, q, J = 7.5Hz), 4.
98 (1H, m), 6.61 (1H, d, J = 8Hz), 6.71 (1H, d, J = 8Hz), 6.90 (1H, s), 6.92
(1H, t, J = 8Hz), 7.10 (1H, t, J = 8Hz), 7.23 (1H, d, J = 8Hz), 7.59 (1H, d,
(J = 8Hz)

Example 1 1- [3-Methoxy-4- (ethoxycarbonylacetyl) benzoyl] -2
, 3,4,5-Tetrahydro-1H-1-benzazepine (1.44 g) and o-
A mixture of phenylenediamine (413 mg) in xylene (20 ml) was refluxed for 50 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol = 10: 1) to give 4- [2-methoxy-4- (2,3
, 4,5-Tetrahydro-1H-1-benzazepin-1-ylcarbonyl) phenyl] -1,3-dihydro-2H-1,5-benzodiazepin-2-one (1
． 32 g) was obtained. NMR (CDCl ₃ , δ): 1.53 (1H, m), 1.89-2.17 (3H, m), 2.71-3.11 (3H, m), 3.38
-3.50 (2H, m), 3.67 (3H, s), 5.03 (1H, m), 6.69 (1H, d, J = 8Hz), 6.82 (1H
, d, J = 8Hz), 6.87 (1H, s), 6.93 (1H, t, J = 8Hz), 7.02-7.12 (2H, m), 7.18-
7.25 (3H, m), 7.34-7.46 (2H, m)

Example 2 4- [2-Methoxy-4- (2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylcarbonyl) phenyl] -1,3-dihydro-2H-1,
Tetrahydrofuran (60 m) of 5-benzodiazepin-2-one (2.27 g)
l) solution in borane-tetrahydrofuran complex (1.
(0M, 12.9 ml) was added at 0 ° C, and the solution was stirred at the same temperature for 3 hours. The cold bath was then removed and the mixture was stirred overnight. 1N hydrochloric acid was added to the reaction mixture and the mixture was stirred for 1 hour. The reaction mixture was basified with sodium hydrogen carbonate, extracted with ethyl acetate and dried over sodium carbonate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 100: 1) to obtain an amorphous substance. Triturate the amorphous material with isopropyl ether to give 2- [2-methoxy-
4- (2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylcarbonyl) phenyl] -2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.3 g) Obtained. NMR (CDCl ₃ , δ): 1.42-1.67 (2H, m), 1.78-2.18 (4H, m), 2.71-2.95 (3H, m),
3.07 (1H, m), 3.38 (1H, m), 3.64 (3H, s), 4.13 (1H, m), 5.04 (1H, m), 6
.65-6.79 (5H, m), 6.86-7.17 (4H, m), 7.21-7.39 (2H, m)

Example 3 2- [2-Methoxy-4- (2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylcarbonyl) phenyl] -2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine (1.0 g) was dissolved in 1N hydrochloric acid (5.0 ml), and the solution was freeze-dried to give 2- [2-methoxy-4- (2,3,4,5-tetrahydro). -1H-1-benzazepin-1-ylcarbonyl) phenyl] -2,
3,4,5-Tetrahydro-1H-1,5-benzodiazepine dihydrochloride (1.0
g) was obtained. NMR (DMSO-d ₆ , δ): 1.92 (1H, brs), 2.08 (1H, brt, J = 8Hz), 2.73-3.16 (4H,
m), 3.58 (3Hx0.5, s), 3.63 (3Hx0.5, s), 3.70 (1H, brs), 3.90 (1H, brs),
4.50 (1H, brs), 4.95 (1H, brd, J = 10Hz), 5.50-5.70 (2H, brs), 6.55-6.78 (
3H, m), 6.94 (1H, t, J = 3Hz), 7.10 (1H, dd, J = 7, 3Hz), 7.16-7.38 (4H, m),
7.47 (1H, brs), 8.08 (1H, brd, J = 3Hz)

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 5/10 A61P 5/10 7/10 7/10 9/00 9/00 9/04 9/04 9 / 12 9/12 13/12 13/12 27/02 27/02 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT , LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM) , KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, C , CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK , SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW

Claims (9)

[Claims] 1. The formula: Wherein R ¹ and R ² together form a benzene, pyridine or thiophene ring, each of which may be substituted with one or more suitable substituents, R ³ is hydrogen or A lower alkoxy group, R ⁴ and R ⁵ are each hydrogen or together form a bond, R ⁶ and R ⁷ are each hydrogen or together form an oxo, R ⁸ And R ⁹ together form a benzene ring, which benzene ring may be substituted with one or more suitable substituents, A represents a lower alkylene group, respectively. ] The compound represented by these, and its pharmaceutically acceptable salt. 2. R ¹ and R ^{2 taken} together form a benzene ring, R ³ is a lower alkoxy group, and R ⁸ and R ^{9 taken} together form a benzene ring. Compound. 3. The compound according to claim 2, wherein R ⁴ and R ⁵ are each hydrogen, R ⁶ and R ⁷ are each hydrogen, and A is tetramethylene. 4. 2- [2-Methoxy-4- (2,3,4,5-tetrahydro-1)
H-1-benzazepin-1-ylcarbonyl) phenyl] -2,3,4,5-
The compound according to claim 3, which is tetrahydro-1H-1,5-benzodiazepine or a dihydrochloride thereof. 5. The formula: Wherein R ¹ and R ² together form a benzene, pyridine or thiophene ring, each of which may be substituted with one or more suitable substituents, R ³ is hydrogen or A lower alkoxy group, R ⁴ and R ⁵ are each hydrogen or together form a bond, R ⁶ and R ⁷ are each hydrogen or together form an oxo, R ⁸ And R ⁹ together form a benzene ring, which benzene ring may be substituted with one or more suitable substituents, A represents a lower alkylene group, respectively. ] A method for producing a compound represented by: or a pharmaceutically acceptable salt thereof, comprising the steps of: 1) a compound represented by the formula: A compound represented by the formula: The compound represented by the formula: (Wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ and A are as defined above, and R ¹⁰ is a lower alkyl group) or a salt thereof. Or 2) Formula A compound represented by the following formula or a salt thereof is reacted with a reducing agent to give a compound represented by the formula: (In the formula, R ¹ , R ² , R ³ , R ⁸ , R ⁹ and A are as defined above.
) A compound represented by or a salt thereof is obtained. 6. With a pharmaceutically acceptable substantially non-toxic carrier or excipient,
A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient. 7. A compound according to claim 1 for use as a medicament. 8. Hypertension, heart failure, renal failure, edema, ascites, vasopressin dyssecretory syndrome, liver cirrhosis, hyponatremia, hypopotassium, which comprises administering an effective amount of the compound according to claim 1 to a human or an animal. A method for treating and / or preventing a visual impairment caused by blood pressure, diabetes, circulatory disorder, cerebrovascular disease, Meniere's syndrome, motion sickness, or ocular circulation disorder. 9. Hypertension, heart failure, renal failure, edema, ascites, vasopressin dyssecretory syndrome, hepatic cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory disturbance in humans or animals of the compound according to claim 1. , Cerebrovascular disease, Meniere's syndrome,
Use for the manufacture of a medicament for treating and / or preventing vision sickness caused by motion sickness or impaired ocular circulation.